Chronic and acute oxygen toxicity is implicated in a growing list of pathologic processes. The three major biopolymers are targets of oxygen toxicity: Nucleic acids, lipids, and proteins. Many proteins are subject to covalent modification by mixed function oxidation. In general, oxidatively modified enzymes lose catalytic activity and become susceptible to proteolytic degradation. Oxidative modification of proteins may have physiological roles. It appears to be the mechanism by which Klebsiella aerogenes controls the metabolic switch from anaerobic to aerobic metabolism. When these cells are switched to an oxygen atmosphere, a rapid oxidative inactivation provides a coordinated response. Glycerol dehydrogenase, ethanol dehydrogenase, and 1,3 propanediol oxidoreductase are inactivated, but the constitutive dehydrogenases remain active. The oxidative inactivation requires synthesis of RNA and protein. The latter may be an oxidase which generates hydrogen peroxide because the coordinated inactivation is also mediated by hydrogen peroxide without protein synthesis. Compounds which specifically oxidize target enzymes may have therapeutic value. The reverse transcriptase and protease of the human immunodeficiency virus are rational targets for such site-specific oxidations. Experiments with the reverse transcriptase demonstrated that it was susceptible to oxidative inactivation. Oxidative modification introduces carbonyl groups into the amino acid side chains of the protein. Derivatization of these carbonyl groups with fluoresceinamine provides a sensitive label for oxidized proteins. Hydrolysis of the labelled protein yielded one major labelled amino acid, the fluoresceinamine derivative of gamma-glutamyl semialdehyde. Oxidation of amino acid homopolymers demonstrated the generation of gamma-glutamyl semialdehyde from arginine, lysine, and proline residues.